Sphingosine-1-phosphate (S1P) represented by the formula (A) is a lipid that is synthesized by the intracellular metabolic turnover of sphingolipids or the extracellular action of secretory sphingosine kinase. It is pointed out that S1P acts as an intercellular and intracellular messenger (Biochem. Pharm., 58, 201 (1999)).

As receptors of S1P, EDG-1 which is a G-protein-coupled receptor and its analogous molecules, EDG-3, EDG-5, EDG-6, and EDG-8 (also called S1P1, S1P3, S1P2, S1P4, and S1P5, respectively) are known. They are called EDG family together with EDG-2, EDG-4, and EDG-7 which are lysophosphatidic acid (LPA) receptors. S1P receptors bind to S1P and deliver signals into cells via G-protein coupled with the receptors. Gs, Gi, Gq, and G12/13 etc. are known as G-proteins to which S1P receptor can couple, and it is considered that the receptor is involved in responses such as increase of cell proliferation, suppression of cell proliferation, induction of cell chemotaxis, and inhibition of cell chemotaxis.
As biological action of S1P, inhibition of migration of smooth muscle cells or cancer cells, platelet aggregation, induction of cell chemotaxis, inhibition of cell chemotaxis, and the like are known in vitro experiments, and as the results of in vitro experiments, it is known that S1P shows effects of controlling blood pressure, promoting angiogenesis, reducing renal blood flow, inhibiting lung fibrosis, promoting the lymphocyte homing into lymphatic organs, and the like. It is considered that those various physiological effects are mediated by S1P receptors existing in cell membrane. However, it has been scarcely clarified excluding some cases which subtypes of S1P receptors mediate these effects in practice.
Recently, from the study for EDG-1 knock-out mice, it is strongly indicated that S1P induced angiogenesis via EDG-1 (J. Clin. Invest., 106, 951 (2000)). Therefore, it is suggested that an EDG-1 agonist is used as an agonist for treating diseases caused by anangioplasia. For example, it is used as an agent for prevention and/or treatment of peripheral arterial disease such as arteriosclerosis obliterans, thromboangiitis obliterans, Buerger's disease, or diabetic neuropathy; varicose vein such as hemorrhoid, anal fissure, or anal fistula; dissecting aneurysm of the aorta, sepsis, inflammatory disease such as angiitis, nephritis, or pneumonia, various edematous disease involved in ischemia of various organ and increase of the blood permeability, for example, myocardial infarction, cerebral infarction, angina, disseminated intravascular coagulation (DIC), pleuritis, congestive heart failure, multiple organ failure, shock with blood incompatibility during blood transfusion, and the like. In addition, the EDG-1 agonist can also be used as an agent for enhancing wound healing of cornea, skin, digestive organs, or the like, or, for example, as an agent for prevention and/or treatment of bedsore, burn, ulcerative colitis, Crohon's disease, or the like. Further, the EDG-1 agonist can also be used as a preoperative, postoperative, and/or prognostic activator for blood vessel accompanying transplantation of various organs, for example, as an adhesion activator of transplanted organs such as heart transplantation, renal transplantation, dermal transplantation or liver transplantation.
On the other hand, EDG-6 is localized and strongly expressed in cells of the lymphatic and hematopoietic systems including spleen, leukocytes, lymph gland, thymus, bone marrow, lung and the like, which suggests the possibility that the EDG-6 is closely related to the effects of S1P in the course of inflammation or in the immune system (Biochem. Biophys. Res. Commun., 268, 583 (2000)).
Moreover, it is known that the EDG-6 polypeptide or its homolog is involved in immunomodulation, antiinflammation and the like in a similar manner as EDG-1, which brings about the potential usability of those substances in treating autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, muscular dystrophy, and the like), allergic diseases (e.g., atopic dermatitis, pollen disease, food allergy, and allergy of chemical drug (e.g., anesthetic such as lidocaine), and the like) allergy, and the like), asthma, inflammatory diseases, infection, ulcer, lymphoma, malignant tumor (e.g., cancer and the like), leukemia, arteriosclerosis, diseases involving lymphocyte infiltration into a tissue, such as multiple organ failure and reperfusion injury after ischemia, shock with blood incompatibility during blood transfusion, and the like.
Meanwhile, it has been known that EDG-8 is mainly expressed in neuronal cells, so EDG-8 can be used for treating various neurodegenerating diseases (e.g., Parkinson's disease, parkinsonian syndrome, Alzheimer's disease, and amyotrophic lateral sclerosis).
Thus, it has been considered that a drug that acts on EDG-1, EDG-6, and/or EDG-8 is useful as a preventive drug and/or a therapeutic drug for rejection to transplantation, transplanted organ abolition, graft-versus-host disease (e.g., acute graft-versus-host disease during bone-marrow transplantation and the like), autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, and muscular dystrophy), allergic diseases (e.g., atopic dermatitis, pollen disease, food allergy, and allergy of chemical drug (e.g., anesthetic such as lidocaine), and the like), asthma, inflammatory diseases, infection, ulcer, lymphoma, malignant tumor (e.g., cancer), leukemia, arteriosclerosis, diseases involving lymphocyte infiltration into a tissue, such as multiple organ failure and reperfusion injury after ischemia, shock with blood incompatibility during blood transfusion, and neurodegenerating diseases (e.g., Parkinson's disease, parkinsonian syndrome, Alzheimer's disease, and amyotrophic lateral sclerosis), and the like.
In recent years, it has been reported that EDG-1 agonist is useful as an immunosuppressant. However, there is no description that EDG-6 agonist or antagonist is useful as an immunosuppressant (see Patent Document 1: WO 03/061567).
On the other hand, it is disclosed that a compound represented by the formula (S):

wherein ArS represents phenyl or naphthyl; AS represents carboxy, or the like; ns represents 2, 3, or 4; R1S and R2S each independently represent a hydrogen atom, a halogen atom, hydroxy, carboxy, C1-6 alkyl which may be substituted by 1 to 3 halogen atoms, or phenyl which may be substituted by 1 to 3 halogen atoms; R3S represents a hydrogen atom or C1-4 alkyl which may be substituted by 1 to 3 hydroxy or halogen atoms; R4Ss each independently represent hydroxy, a halogen atom, carboxy, or the like; CS represents C1-8 alkyl, C1-8 alkoxy, phenyl, or the like or CS is nil; and BS represents phenyl, C5-16 alkyl, or the like (only necessary parts of the definitions of the symbols are extracted);
a pharmaceutically acceptable salt thereof and a hydrate thereof, and
a compound represented by the formula (T):

wherein ArT represents phenyl or naphthyl; AT represents carboxy, or the like; mT represents 0 or 1; nT represents 0 or 1; R1T and R2T each independently represent a hydrogen atom, a halogen atom, hydroxy, carboxy, C1-4 alkyl or phenyl which may be substituted by a halogen atom, or the like; R3T represents a hydrogen atom, C1-4 alkyl which may be substituted by hydroxy or a halogen atom, or the like; R4T's each independently represent a halogen atom, C1-4 alkyl, C1-3 alkoxy, or the like; CT represents C1-8 alkyl, C1-8 alkoxy, phenyl, or the like or CT is nil; and BT represents phenyl, C5-16 alkyl, or the like (only necessary parts of the definitions of the symbols are extracted);
a pharmaceutically acceptable salt thereof, and a hydrate thereof are useful as EDG-1 agonists (see Patent Document 2: WO 03/062248 and Patent Document 3: WO 03/062252).
On the other hand, it is disclosed that a carboxylic acid derivative represented by the formula (Z):

wherein R1Z represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro, or trifluoromethyl; ring AZ represents a C5-7 monocyclic carbocyclic ring or a 5- to 7-membered monocyclic heterocyclic ring containing one or two nitrogen atoms, one oxygen atom and/or one sulfur atom; EZ represents —CH2—, —O—, —S— or —NR6Z—, in which R6Z represents a hydrogen atom or C1-8 alkyl; R2Z represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro or trifluoromethyl; R3Z represents a hydrogen atom or C1-8 alkyl; R4Z represents a hydrogen atom or C1-8 alkyl, or R2Z and R4Z may be taken together to form —CH2CH2— or —CH═CH—; GZ represents —CONR7Z—, —NR7ZCO—, —SO2NR7Z—, —NR7ZSO2—, —CH2NR7Z— or —NR7ZCH2—, in which R7Z represents a hydrogen atom, C1-8 alkyl, or the like; QZ represents C1-4 alkylene or the like; pZ represents 0 or an integer of 1 to 5; qZ represents an integer of 4 to 6; rZ represents 0 or an integer of 1 to 4; and  represents a single bond or a double bond, a prodrug thereof, or a non-toxic salt thereof is known as an EDG-1 agonist (see Patent Document 4: WO 02/092068).
Moreover, it is disclosed that a compound represented by the formula (Y):

wherein ring AY represents a cyclic group; ring BY represents a cyclic group which may further have a substituent(s); XY represents a bond or a spacer which has a main chain having 1 to 8 atoms in which one atom in the spacer may be taken together with a substituent on ring BY to form a ring group which may have a substituent(s); YY represents a bond or a spacer which has a main chain having 1 to 10 atoms in which one atom in the spacer may be taken together with a substituent on ring BY to form a ring group which may have a substituent(s); ZY represents an acidic group which may be protected; nY represents 0 or 1, wherein when nY is 0, mY represents 1 and R1Y represents a hydrogen atom or a substituent, and when nY is 1, mY is 0 or an integer of 1 to 7 and R1Y represents a substituent in which when mY is 2 or more, a plurality of R1Y s are the same or different from each other, a salt thereof, a solvate thereof, or a prodrug thereof has an S1P receptor binding ability (see Patent Document 5: WO 2005/020882).
Patent Document 1: WO 03/061567
Patent Document 2: WO 2003/062248
Patent Document 3: WO 2003/062252
Patent Document 4: WO 2002/092068
Patent Document 5: WO 2005/020882